Methodology gaps in Medicine

Representative open questions

Showing 30 of 812 — one per source paper, highest-quality first.

• Gut microbiota in chronic kidney disease-mineral and bone disorder: shared mechanisms, disease-specific signatures, and therapeutic prospects (2026) · doi

  There is a need for standardized strain selection methods in microbiota interventions for CKD-MBD, with specific focus on the Erysipelotrichaceae and Clostridium sensu stricto taxa.

• Heart-brain axis pathophysiological understanding and clinical impact (2026) · doi

  The molecular imaging techniques used to investigate the brain-heart axis and cardiac dysfunction after cerebral ischemia (reference 113) have not been systematically compared across different imaging modalities or validated in longitudinal cohorts to establish standardized protocols for clinical implementation.

• CUIDADO TRANSICIONAL HOSPITAL-DOMICÍLIO REALIZADO POR ENFERMEIRAS A PESSOAS IDOSAS COM MARCAPASSO ARTIFICIAL: PROTOCOLO DE REVISÃO DE ESCOPO (2026) · doi

  The scoping review protocol does not specify a critical quality assessment methodology for evaluating the methodological quality of included studies on transitional hospital-to-home nursing care for elderly patients with artificial pacemakers. While the authors mention that quality evaluation will not be performed per JBI guidelines for scoping reviews, potential methodological limitations in the primary studies will only be described in the synthesis without formal assessment tools.

• The impact of traumatic injury on the respiratory system; a narrative review of injury-associated and clinically-induced mechanisms of trauma-associated pneumonia (2026) · doi

  Supine body positioning has been identified as a risk factor for ventilator-associated pneumonia in mechanically ventilated patients, but the specific effects of patient positioning on microaspiration and bacterial colonization in trauma patients with multiple rib fractures and altered chest wall mechanics have not been rigorously studied.

• FDG-PET/CT based small volume accelerated immuno chemoradiotherapy in locally advanced NSCLC (PACCELIO) – a randomized, open-label, multicenter phase II trial protocol (2026) · doi

  The trial prospectively evaluates immunomarkers (NLR, ALI) and immune-related radiotherapy planning parameters (EDIC, PET-related imaging parameters) in NSCLC, but the specific mechanistic relationships between these biomarkers and response to hypofractionated, accelerated chemoradiotherapy combined with consolidative immunotherapy have not been established. The longitudinal kinetics of these immunomarkers during the condensed treatment schedule require quantitative correlation analysis with clinical outcomes.

• Impact of Health Education and Preventive Interventions on Non- Communicable Diseases in Rural Communities: A Community-Based Randomized Controlled Trial (2026) · doi

  The intervention group achieved significant systolic blood pressure reduction (14.45 mmHg) and BMI reduction, but the paper does not disaggregate which components of the structured lifestyle counseling—dietary education, physical activity promotion, or medication adherence counseling—drove these improvements in obesity-related hypertension treatment.

• Integration of biomedical imaging and sensing technologies with AI-IoT for Materiovigilance and predictive modeling of stillbirth risk in maternal-fetal health monitoring (2026) · doi

  AI prediction models using ensemble methods (XGBoost, gradient boosting, random forest) demonstrate variable sensitivity and specificity across studies, with one XGBoost model showing only 25% sensitivity. Feature selection strategies and model optimization techniques specific to stillbirth prediction datasets remain inadequately developed.

• Activation of anti-inflammatory pathways by polyunsaturated fatty acid signaling may protect neurodevelopment in children prenatally exposed to methylmercury (2026) · doi

  The use of different donors for placenta and cord blood samples prevented direct comparison between tissue types and limited conclusions about prenatal mercury exposure dynamics. Future investigations should employ paired fetal-maternal tissue samples (placenta and cord blood from the same individual) to enable direct assessment of oxylipin metabolite patterns across compartments and establish temporal relationships in mercury exposure.

• Neurosurgery as an immune anchor point: a translational framework for perioperative immunoengineering (2026) · doi

  The paper references tissue biorepository infrastructure for clinical translation but does not specify standardized protocols for longitudinal immune profiling of perioperative neuroimmune changes in neurosurgical patients. Comparative characterization of macrophage subsets at the meningeal margin across different surgical procedures and timepoints post-resection is needed to establish mechanistic benchmarks.

• The neuro-immune axis in preeclampsia: from the maternal-fetal interface to systemic dysregulation (2026) · doi

  The paper proposes that targeted modulation of central autonomic or sensory integration circuits may reduce neurological manifestations such as eclampsia or cerebral autoregulation failure in preclinical models, but does not specify which circuit targets (e.g., nucleus tractus solitarius, dorsal motor nucleus, insular cortex) should be prioritized or what modulation techniques (optogenetics, chemogenetics, pharmacological interventions) should be tested.

• The use of artificial intelligence based modelling techniques in One Health-related infectious disease studies in Sub-Saharan Africa: a review (2026) · doi

  The review protocol was not prospectively registered in a public registry such as PROSPERO prior to conducting the systematic literature search, limiting the transparency and reproducibility of the review methodology.

• Autologous Platelet Concentrates in Sports Medicine: Mechanisms of Tissue Regeneration and Clinical Applications – A Narrative Review (2026) · doi

  Clinical studies of autologous platelet concentrates frequently omit complete biologic characterization including baseline whole-blood characteristics, final platelet/leukocyte/erythrocyte composition, activation method details, and growth factor quantification; standardized reporting of these preparation variables is necessary for cross-trial comparison.

• What is The Effect of Early Enteral Nutrition on Mortality in Critically Ill Patients Receiving Vasopressor Support? : A Systematic Review (2026) · doi

  Multiple studies identified varying vasopressor dose thresholds for safe enteral nutrition initiation (≤0.14 µg/kg/min by Merchan et al., <0.3 µg/kg/min by Luping Wang et al., 0.23 µg/kg/min by Fan Qi et al.), but no prospective study has prospectively validated which norepinephrine-equivalent dose cutoff, in combination with clinical perfusion parameters, reliably predicts enteral feeding tolerance and prevents mesenteric ischemia across different patient populations.

• Decision-ready evidence for vital pulp therapy: a network meta-analysis of bioactive materials in mature permanent teeth (2026) · doi

  Diagnostic thresholds for symptomatic teeth in vital pulp therapy studies were heterogeneous, introducing classification noise that could not be fully eliminated even with composite outcome definitions and sensitivity analyses. Standardized diagnostic criteria and symptom severity scales (e.g., Visual Analogue Scale pain scoring, percussion response grading) should be adopted prospectively in RCTs comparing pulpotomy outcomes in symptomatic mature permanent teeth.

• Exercise benefits in metabolism on cardiovascular disease (2026) · doi

  High-throughput proteomics have uncovered exercise training and type 2 diabetes-induced changes in human white adipose tissue, but comparative proteomic analysis across different exercise modalities, duration, and intensity levels in cardiovascular disease populations has not been systematically characterized to identify tissue-specific biomarkers.

• What is the diagnostic accuracy of different clinical diagnostic criteria (Rotterdam, NIH, and Androgen Excess Society) for identifying polycystic ovary syndrome in women of reproductive age? : A Systematic Review (2026) · doi

  Technical standardization for follicle counting and ovarian volume measurement remains unspecified; differences in ultrasound equipment quality, operator training, counting protocols, hormone assay methods, calibration standards, and reference ranges across study sites require establishment of standardized measurement protocols and operator certification requirements to reduce technical variation in PCOS diagnostic accuracy.

• Effectiveness of screening modalities for early detection of diabetic retinopathy: a systematic review and meta-analysis of tele-ophthalmology, AI-based tools, and conventional methods (2026) · doi

  Reporting of DR screening modality studies has focused predominantly on screening coverage and uptake; cost-effectiveness analysis, healthcare system resource allocation impacts, and clinical decision-making integration of AI versus conventional methods require systematic comparison.

• Management of depression utilizing Traditional Chinese Medicine (2026) · doi

  Non-pharmacological TCM modalities such as acupuncture and herbal baths are clinically promising for depression symptom relief but demand deeper mechanistic scrutiny, including reproducibility of neurochemical changes and determination of pharmacokinetic profiles of active agents in these delivery systems.

• The Relationship between a History of Cesarean Section and The Incidence of Placenta Accreta : A Systematic Review (2026) · doi

  Serum amyloid A (SAA) was found elevated in both placenta previa and accreta groups but could not distinguish previa from accreta alone. Additional biomarker studies combining SAA with other inflammatory or decidualization markers (e.g., endometrial thickness, vascular markers) in prospective cohorts are needed to develop a diagnostic panel for PAS risk stratification.

• A systematic review of sample size determination in Bayesian randomized clinical trials: full Bayesian methods are rarely used (2026) · doi

  The adaptive platform trial designs documented (HEALEY ALS Platform Trial, REMAP-CAP, PRINCIPLE trials) use hybrid or unspecified sample size methods, but there is insufficient evidence on optimal Bayesian sample size determination strategies specifically designed for multi-arm, multi-stage adaptive platform trial architectures with shared control arms.

• Unveiling the relationship of the comorbidity between depression and type 2 diabetes mellitus: a macro analysis and micro interpretation (2026) · doi

  Bibliometric tools currently lack the capability to differentiate between author names with identical abbreviations in depression and T2DM comorbidity studies. Developing disambiguation algorithms specifically trained on medical literature author datasets would improve accuracy of author contribution tracking and citation analysis in this research domain.

• A behaviour and disease model of testing and isolation (2026) · doi

  The model does not incorporate severe case outcomes (hospitalisations and deaths) despite population perception of illness threat potentially varying by case severity over an outbreak. Refinement is needed to include hospitalisation and death dynamics, with parameterisation of how the population's behavioural response shifts when attributed different importance to cases versus hospitalisations versus deaths.

• Artificial intelligence in acute and critical care: current challenges and strategic solutions (2026) · doi

  Fine-tuning combined with retrieval-augmented generation for error-detection and self-correction capabilities in AI systems for acute and critical care requires systematic evaluation and validation. The paper identifies this as a needed approach but does not specify implementation protocols, benchmark datasets, or performance metrics for testing these combined techniques in complex clinical scenarios.

• Peran Tenaga Kesehatan dalam Penanganan Penyakit Degeneratif pada Lansia di Puskesmas Negeri Lama: Sebuah Studi Kasus (2026) · doi

  Mixed-methods research combining in-depth interviews with elderly patients and families alongside quantitative measurement of quality of life using WHOQOL-BREF or EQ-5D questionnaires and clinical outcomes (blood pressure, blood glucose) has not been conducted to capture both patient perspectives and objective health metrics in degenerative disease management at primary health centers.

• Artificial intelligence approaches to predicting treatment non-adherence in chronic diseases: a narrative review (2026) · doi

  The literature demonstrates considerable heterogeneity in disease contexts, data sources, model architectures, and adherence outcome definitions across chronic disease adherence prediction studies, which constrains direct comparison of machine learning model performance. Standardized frameworks for defining adherence outcomes and model evaluation metrics across diverse chronic conditions are needed to enable systematic benchmarking.

• Evidence-based approaches for Empty Nose Syndrome management: a systematic review highlighting current treatments and future directions (2026) · doi

  Objective evaluation metrics for Empty Nose Syndrome treatment outcomes require development and validation to be consistently applied across different studies; solutions such as using natural disease progression as a control and independent assessor blinding need implementation but lack specific operational definitions.

• Multimodal artificial intelligence in urologic precision oncology: from algorithm to translational medicine (a systemized narrative review) (2026) · doi

  Multimodal AI systems for prostate cancer diagnosis require clinician participation in development (reference 48), yet the specific frameworks, validation protocols, and training methodologies for ensuring effective human-AI collaboration between urologists, pathologists, and radiologists have not been comprehensively defined.

• Biochemical Markers In Seminal Plasma And Serum: A Comparative Assessment In Fertile And Infertile Men (2026) · doi

  Standardized protocols for biomarker evaluation in seminal plasma and serum—including sample collection, processing, and analysis procedures—are necessary to convert research findings on male fertility markers (SGOT, LDH, cholesterol, copper, glucose) into clinical practice and enable integration into standard clinical procedures.

• Protocol for non-invasive assessment of skeletal muscle structure and function in adolescents with single ventricle heart disease: a cross-sectional, case-control study (2026) · doi

  The current study design is cross-sectional and prohibits identification of causality between skeletal muscle deficits and adverse outcomes in SV patients. Longitudinal studies tracking skeletal muscle structure and function changes over time in adolescents with single ventricle physiology are needed to establish causal relationships.

• Cardiovascular Risk Prediction Using Machine Learning: Advances and Clinical Translation (2026) · doi

  Participatory design approaches involving clinicians in cardiovascular risk model development and validation have been linked to higher adoption rates, but the paper lacks specific guidance on which aspects of model development (feature selection, threshold calibration, output formatting) should be clinician-guided and how to measure clinician trust quantitatively during participatory design iterations.